This application describes a five year research career development program in the study of mechanisms of Ras transformation in a model mammalian system. The candidate is trained in Adult Oncology and has a Ph.D. in genetics. The mentor is Professor Tyler Jacks, Director of the Center for Cancer Research and Professor of Biology at the Massachusetts Institute of Technology. Dr. Jacks is a world leader in dissecting molecular pathways responsible for tumorigenesis using novel mouse cancer models. The proposed research program will provide training in developmental and cancer biology, both new fields of research for the candidate, in preparation for a career as an independent physician-scientist. Activating mutations in Ras oncogenes occur frequently in a variety of human cancers, including one third of lung adenocarcinomas. Despite several decades of intense study, the molecular basis of Ras oncogenicity is incompletely understood. The underlying hypothesis of this proposal is that the study of oncogenic Ras signaling in development will reveal important and novel mechanisms of Ras transformation, and may lead to new strategies for the prevention and treatment of Ras malignancies. The candidate recently generated mice carrying an endogenous, oncogenic allele of K-ras. These mice exhibit striking developmental defects and early embryonic lethality. This proposal seeks to test several hypotheses regarding how oncogenic K-ras and its associated negative regulators contribute to this developmental phenotype and to tumorigenesis. Aim 1 will identify and characterize the primary developmental defects induced by oncogenic K-ras using conditional targeting strategies and tetraploid complementation. Aim 2 will examine the role of Sprouty proteins and other Ras/MAPK antagonists in mediating the embryonic lethal phenotype associated with oncogenic K-ras. Aim 3 will test whether induction of Ras/MAPK antagonists plays a role in Ras transformation in vitro and Ras-induced lung tumorigenesis in vivo.